These studies are designed to increase our understanding of the neurochemical mechanisms that are relevant to cocaine and opioid abuse. Cocaine and opioids such as morphine and heroin are widely abused substances that activate dopamine rich regions of the brain, and there are many studies suggesting involvement of opioid systems in the actions of psychomotor stimulants. Anatomical studies demonstrate that dopaminergic terminals are co localized with opioid receptors and opioid peptides in many brain regions. In animal models, cocaine induced reinforcement is attenuated by either dopamine or opioid antagonists, suggesting that both systems are involved in the effects of cocaine. The specific objective of this project is to examine whether there are functional changes in opioid receptors in rat brain following treatment with cocaine, morphine, or opioid antagonists. Since opioid receptors are negatively coupled to adenylyl cyclase (opioids will inhibit cyclase activity), it is possible to measure changes in the function of opioid receptors in vitro. Chronic treatment with an opioid receptor antagonist, such as naltrexone, produces an increase in the number of mu opioid receptors in the brain. Recent studies in our laboratory have shown that there are also increases in the function of opioid receptors following chronic naltrexone administration. We have also shown that there are increases in these receptors following chronic, continuous administration with cocaine, but that these changes are limited to specific brain regions. Furthermore, the magnitude of the changes appear to be different following daily injections of cocaine (a treatment regimen that produced behavioral sensitization) than after continuous infusions of cocaine (a regimen that produced behavioral tolerance). These findings are being further investigated. These findings suggest that the opioid system may play an important role in the behavioral effects produced by cocaine and may serve as a target for the development of medical therapies for cocaine abuse.